Steroid nitrite esters



United States Patent 3,215,713 STEROID NITRITE ESTERS Derek H. R. Barton, Northwood, England, assignor, by

mesne assignments, to Schering Corporation, Bloomfield, N J., a corporation of New Jersey No Drawing. Filed Mar. 14, 1961, Ser. No. 95,490 16 Claims. (Cl. 260397.4)

This application is a continuation-in-part of my copending application Serial No. 19,444, filed April 4, 1960, now abandoned.

The present invention relates to a new photolytic process and to new compounds for use in such a process. More particularly, it relates to a novel and improved process for attaching substituents to the 18 to 29 carbon steroids and to other organic compounds.

The present invention has for its object the provision of a novel and improved process by which various substituents may be attached to different and selected portions of the molecule of certain organic compounds, which organic compounds are selected from the group of alcohols having a first carbon atom to which the OH group is attached, a carbon atom adjacent said first carbon atom, another atom spaced from said first carbon atom by said adjacent carbon atom, and attached to said other atom another carbon atom to which at least one hydrogen atom is attached, said other atom being selected from the group consisting of O, S, N, and C. This group of alcohols may be symbolized by HO-CCXCH, wherein X is C, O, N, and S, said group of alcohols being further characterized by being selected from the group consisting of the heterocyclic, alicyclic (including steroids) and other cyclic alcohols, and those other alcohols which have at least six carbon atoms and another atom selected from the group consisting of O, S, N, and C. As used hereinafter, the expression HOCCXCH alcohols is used to include those alcohols which are comprised within the foregoing definition.

A further object of the present invention is the provision of a novel and improved process of photolysis which is applicable to solutions of the nitrite esters of such HOC-CXCI-I alcohols.

The invention further provides a novel and improved process of forming many new organic compounds, many of which are new and useful in themselves, while others of the resulting compounds are steroids useful as intermediates in the production of different steroids and other organic compounds many of which have medicinal value. In many instances, the process of the present invention makes it possible to form substituted compounds which cannot be formed by conventional processes, while in other instances, the process of the present invention provides a simpler, more expedient and more economical process of forming such substituted organic compounds.

A further object of the present invention, in certain of its aspects, is the provision of a novel and highly useful series of new compounds, the nitrite esters of steroids having from 18 to 29 carbon atoms, which are characterized by being photochemically active, and by having the nitrite radical in the 1,6, 25, 4 3, 6 3, 715, 11a, llfl, 15a, 18, 19, 20a 20 8, or 24 position. Such nitrite steroid esters provide a series of compounds which are extremely useful as intermediates and may be photolytically reacted to produce oximes, nitroso-monomers and nitroso-dimers and in some instances, by further chemical change, nitrones.

In the process of the present invention, there is first formed the nitrite ester of a HO-CCX-CH alcohol, as by reacting such an alcohol with nitrosyl chloride in a dry non-polar solvent, such as pyridine, after which the nitrite ester is subjected to ultraviolet radiation of a wave length band from about 3000 A. to 5000 A. while the nitrite ester is dissolved in a suitable solvent. The wave lengths of the irradiation band are such that it includes activating energy, and the wave length of the ultraviolet light corresponds to at least some of the absorption bands of the nitrite radical. This activation of the nitrite radical causes the NO group to be transferred from the carbon atom to which it is linked to a conformationally adjacent carbon atom; the resultant chemical change is that NO group is exchanged with an H atom originally attached to this conformationally adjacent carbon atom. The latter carbon atom is separated from the carbon atom to which the nitrite radical is linked by two intervening carbon atoms or by a -C-X group. wherein X is O, S, or N. Thus, by irradiation and photolysis, the nitrite is transformed by rearrangement of the molecule into an oxime, a nitroso-dimer, or a nitroso-monomer, and occasionally if other functional groups are suitably placed, to a small extent to a nitrone. The oxime, nitroso-monomer and the nitroso-dimer, as well as any nitrone which is formed, may then be further reacted to form other organic compounds, such as lactones, hemi-acetals, nitriles, alcohols, aldehydes, ketones, amines, carboxylic acids, iminolactones, and many other derivatives.

The process of the present invention, in its broadest aspect involves the photolytic exchange of a hydrogen atom and a NO group within the molecule of an HOC-CXCH alcohol, the interchange being effected between the NO group and a hydrogen which are linked to separate carbon atoms, which carbon atoms are spaced from each other by two other atoms one of which is carbon while the other is oxygen, sulfur, nitrogen or carbon, the hetero-atom being more distant from the OH group than the others of the two spacing atoms. With such an arrangement of the NO group and a hydrogen atom attached to separate carbon atoms within the molecule subjected to ultra-violet radiation of a wave band including ultra-violet energy of wave lengths corresponding to at least some of the absorption bands of the nitrite radical, the nitrite radical is activated and, when the and Fieser, Steroids (1959), pp. 7 to 15, and the works there referred to, the atoms attached to the 11,8 and 18 carbon atoms are more adjacent to each other than the 11,8 substituents are to the hydrogen atoms attached to carbon atoms at positions 8, 9, 12 or 13. Similarly, the substituents on the 11,8 are closer to the hydrogen atoms on the 19-carbon atom, than they are to the other hydrogen atoms attached to the carbon atoms surrounding the 19-carbon position, that is to the hydrogen atoms attached to carbon atoms at positions 1, 5, 6, or 9.

In a similar manner, the atoms and groups linked to other carbon atoms in the steroid molecule, are conformationally adjacent to the hydrogen atoms linked to certain other carbon atoms, of which the following are the principal examples: 1 8 group is conformationally adjacent to hydrogen attached to ll-carbon;

218 group is conformationally adjacent to hydrogen attached to 19-carbon;

45 group is conformationally adjacent to hydrogen attached to 19-carbon;

65 group is conformationally adjacent to hydrogen attached to 19-carbon;

tached to 15-carbon;

115 group is conformationally adjacent to hydrogen attached to 18- and l9-carbons;'

11a group is conformationally adjacent to hydrogen attached to l-carbon;

1500 group is conformationally adjacent to hydrogen attached to 7-carbon;

18 group is conformationally adjacent to hydrogen attached to ll-carbon;

19 group is conformationally adjacent to hydrogen attached to I l-carbon;

20a and 20;; groups are conformationally adjacent to hydrogen attached to lS-carbon;

24 group is conformationally adjacent to hydrogen attached to 20-carbon.

In less complex compounds to be conformationally adjacent, it is usually only necessary that the photolytically active nitrite group be linked to a carbon atom of a compound having the grouping ONOCC-X-CH, such as l-octanol-nitrite, (l-octyl nitrite), and the carbon holding the reactive hydrogen to be exchanged with the NO group will be found to be spaced from the carbon atom to which the NO group is attached by two intervening carbon atoms or by by two atoms C'X wherein X is O, N, or S, provided the carbon possessing the reactive hydrogen is saturated. Thus, in the case of l-octyl nitrite, irradiation of the compound in a suitable solvent, will cause the NO group, at the 1-position, to be exchanged with a hydrogen attached to the 4-position. Similarly, an NO group attached to the 2-carbon in the nitrite ester of 2-octyl alcohol will react with a hydrogen atom attached to the S-carbon atom.

After the process has been carried out, as by the formation of oxime at the 4-position from a nitrite ester having the nitrite group in the 1-position, the oxime may be converted to the corresponding alcohol, giving a 1,4-diol, which may then be re-esterified to yield the 4-nitrite ester, which may then be subjected to further photolysis in solution to yield the oxime at the 7-position, which 7- oximino compound may then be converted into the desired final product, such as a 1,4,7-triol.

The mechanism by which this photolytic rearrangement and exchange takes place is imperfectly understood at the present time, but the following model and explanation is offered, which is consistent with the facts known at the present time.

A primary, secondary, tertiary, normal or branched chain nitrite, derived from an HOC-CXCH alcohol, represented by the general Formula 1 below, and illustratively having eight carbon atoms in the molecule, is subjected to ultra-violent irradiation of a wave-band having wave-lengths in the general range of 3000 A. to 5000 A., and preferably intense bands of radiation between 3400 A. and 4000 A., which correspond to at least some of the ultraviolet absorption bands of the nitrite radical, in the solvent being used, whereupon, the NO group bonded as shown in Formula 2, is freed from the oxygen atom linking it to its original carbon atom in the molecule. The hydrogen atom on the fourth carbon atom (that is the carbon atom which is separated by two carbon atoms from the carbon atom to which the nitrite group is attached) is attacked by and thence held by the ultra-violet activated oxygen radical generated by release of the NO group as shown in Formula 3. The next page is thought to comprise the migration of the NO group to the carbon group from which the hydrogen was just released as shown in Formula 4, and which may exist as a monomer or dimer depending on the structure of the compound, and Where R or R in the Formulae l, 2, 3, and 4, or both of them is hydrogen, the reaction proceeds under prototropic conditions (preferably in a lower alkanol solution at reflux temperature) to the formation of the oxime after which removal of one molecule of water will result in the formation of a nitrile (6) (if R is hydrogen).

As applied to aromatic and other aryl compounds the nitrite radical, as in (7), by photolysis is rearranged to form a nitrosodimer compound, such as in (8a) which converts under prototropic conditions to the more stable isomer, the oxime (8b).

With alicyclic compounds, the nitrite group may be attached to a carbon in the ring, as at (9), and react with an available hydrogen separated from the nitrite radical by four carbon atoms (that is by two carbon atoms intervening between the carbon atoms to which the nitrite radical and reactive hydrogen are attached to give a compound such as (10a) and the isomeric oxime (10b); or, in an aromatic compound, the nitrite radical in the side chain ('11) may react with a hydrogen bonded to alczabrbon atom in another side chain to yield (12a) and ti a ( H oNo CHzONO OHzOH (10b) OH H2 =N O H (12a) CHzOH CHzNO b) ICHZOH CIJ=NOH Similarly, in the heterosubstituted compounds the nitrite radical (in Compound 13) is activated by irradiation to exchange its NO group with a hydrogen suitably spaced from the nitrite-bonded carbon atom, to give the compound shown at (14).

In other heterosubstituted compounds the nitrite esters photolyze in solution to cause a transfer of the NO group from one carbon atom to the conformationally adjacent carbon atom which is the fourth carbon atom, or the fourth atom in the group HO-C--C-XCH, where X is oxygen, sulfur, nitrogen or carbon.

- Typical of such other hetenosubstituted compounds Whose nitrite esters are subjected to photolysis in solution are the nitrite ester of B-diethylamino-a-phenylethyl alcohol (15) which is photolysed to form fi-(ethyl-a-nitro soethyl) amino-u-phenylethyl alcohol dimer (16a) and the isomeric oxime (16b); the nitrite ester of l-(p-chloro-mphenyl benzyl) 4-(2-hydr0xyethoxyethyl)-piperazine (17) which on photolysis in solution will yield 1-(pchloro-u-phenylbenzyl) 4 (Z-hydroxyethoxy-B-nitrosoethyl)piperazine dimer (18a) and the isomeric l-(pchloro-a-phenylbenzyl) 4-(Z-hydrQXyethoXy-B-oximinoethyl)piperazine (18b); and the nitrite ester of propyl- (fl-hydnoxy-v-chloropropyl)sulfide (19) which on photolysis yields (a-nitrosopropyl)-( 8-hydroxy-'y-chloropropyl) sulfide (20a) and the isomeric oXime (20b) (ocoximinopropyl)-(B-hydroxy-y-chloropropyl) sulfide.

' The process of the present invention now finds its greatest field of usefulness in the preparation of novel steroids, having from 18 to 29 carbon atoms, in that it provides a novel manner of general application by which substituents may be added to the steroid molecule, in positions where heretofore great difliculty has been experienoed, and in many instances it provides the unique manner of providing certain substituents at certain positions.

In the process of the present invention, as it is applied to the 18 to 29 carbon steroids, there is first formed a nitrite ester having a nitrite radical in the 1, 2, 4, 5, 6, 7, 11, 15, 18, 19, 20 or 24 position, by reacting a solution of a steroid having a hydroxy group at the corresponding position in pyridine, dimethylformamide, acetic anhydride or other non-polar solvent with a nitrosyl halide, preferably nitrosyl chloride. The steroid nitrite so formed is then subjected to ultraviolet radiation which includes a band of radiation corresponding to at least some of the adsorption bands of the nitrite radical. This irradiation causes the nitrite radical to be activated so that the NO group is transferred from a carbon atom of the steroid molecule to a conformationally adjacent carbon atom spaced from the carbon to which the nitrite group is linked by two carbon atoms (as from the 115 to the 18 position), to form a compound which may then be further reacted in various Ways by conventional procedures.

Many of the nitrite esters used in the process of the present invention are new and valuable intermediates, and the invention thus also comprises such novel nitrite esters, especially the nitrite esters of steroids having from 18 to 29 carbon atoms, and in which the nitrite ester is in the 1,8, 2,9, 4 6,6, 7 11p, 150:, 1813, 19,3, 200:, 20s, or 24 position. In the 2B, 45, 6,3, and position, the nitrite radical is oonformationally adjacent to a hydrogen attached at the 19 position. In the 1B, 18, and 19 positions, the nitrite is conformationally adjacent to a hydrogen attached to the '11 position. In the 11B, 200: and 20 8 positions, the nitrite is conformationally adjacent a hydrogen in the 18 position, while in the Ila-position, the nitrite is conformationally adjacent a hydrogen in the 1- position; in the 7fl-po'sition, the nitrite is conformationally adjacent a hydrogen in the 15-p0sition; in the 15 Ot-pOSliliOn, the nitrite radical is conforrnationally adjacent a hydrogen in the 7-position, while in the 24 position the nitrite radical is conformationally adjacent a hydrogen in the 20 position of a steroid having from 24 to 29 carbon atoms.

The 18 to 29 carbon steroid nitrites of the present invention thus form a group of valuable and highly useful intermediates for the production of both known and hitherto unknown steroids, while the process of the present invention provides a novel method by which a variety of substituent groups may be introduced at many different posit-ions, including the 1'1, 18, 19, and 20 positions into a steroid molecule having 18 to 29 carbon atoms, thereby providing a series of intermediates which serve for the formation of other compounds, many of which have heretofore been difiicult to prepare, while others have been unknown and cannot be made by known or conventional processes.

Among the types of organic compounds which can be usefully employed as starting materials in the process of the present invention are the 18- to 29-carbon steroids, having a hydroxy group, such as llfi-hydroxyestrone, 1 lfl-hydroxy-A androstene-3,17-dione, 1 1 B-hydroxytestosterone-l7-acetate, 1'1li-hydroxyisoandrosterone-3-acetate, cortisol acetate, corticosterone acetate, l6a-hydroXy-c0rticosterone acetate, 16a-methyl corticosterone acetate, IGB-methylcorticosterone acetate, 16a-hydroxy-1-dehydrocorticosterone acetate, 16ix-methyl-l-dehydrocorticosterone acetate, l6fi-methyl-l-dehydrocorticosterone acetate, pregnane-3a,11/3,l7e,20 8-tetr0l-3,20 diacetate, prednisolone acetate, ll 3-hydroxyprogesterone acetate, 115,170:- dihydroxyprogesterone, l6a-hydroxyprednisolone acetate, l6a-methylprednisolone acetate, 16,8-methylprednisolone acetate, dexamethasone acetate, 16-epi dexamethasone acetate (A -pregnadiene-3,20-dione-9u-fluoro-11fi,17u,21- triol-16B-methyl 21 acetate), pregnane-3u,l 1;3,20-triol 3a,20-diacetate and llfl-hydroxy cholestanol acetate.

Certain of these compounds, such as some of those having one or more additional hydroxy groups, may need preliminary protection to block some of the hydroxy groups, so that these hydroXy groups will not react with the nitrosyl halide.

While the nitrosyl chloride or nitrosyl bromide used to form the nitrite may be added to the alcohol solution in any desired manner, it is convenient slowly to add a solution of the nitrosyl chloride in the same solvent as is used to dissolve the alcohol, or alternatively, the nitrosyl chloride may be introduced as a gas into the solution of the alcohol. The solvents are preferably dry non-polar solvents, such as pyridine, acetic anhydride or dimethylformamide.

The formation of the organic nitrite is usually very rapid, and the progress of the reaction is usually observed by the resulting color of the solution, so that when the blue green or other color of the nitrosyl chloride is no longer discharged or changed by reaction with the dissolved alcohol, it can be assumed in general that the nitrite has been formed and that the compound in the solution is ready for separation and photolysis.

In the majority of the reactions within the scope of the present invention, the temperature at which the nitrite is formed is not subject to any critical range but the reactions are usually carried out at moderate temperatures, ranging from 30 to 30 0, although in certain of the reactions the yield varies when there is a departure from an optimum temperature. In general satisfactory results have been found to result from carrying out the nitrosyl chloride reactions in the neighborhood of C. to 30 C. and generally at 1'5 C. to 20 0, although the reaction will proceed over a Wide temperature range, such as 30 C. to i+30 C.

After completion of the formation of the nitrite, the

nitrite is separated, and this is generally accomplished by adding Water to the solution to precipitate the nitrite and by subsequent filtering, followed by crystallization, and recrystallization if desired, or otherwise if the nitrite is a liquid.

Thereafter, the nitrite is dissolved in a solvent preparatory to being subjected to photolysis by ultraviolet light, although a liquid or solid nitrite ester of this invention may be photolysed per se and there will occur a transfer of the N0 group with said active hydrogen according to this invention.

The ultraviolet radiation used to activate the nitrite radical so as to cause it to be transferred in part to replace the adjacent hydrogen attached to a carbon atom, is that band of radiant energy which corresponds to some or all of the ultraviolet absorption bands of the nitrite radical and is in the range from 3000 A. to 5000 A. and usually at 3400 A. to 4000 A. Such energy is conveniently supplied by a Hanovia high-pressure mercury arc lamp with a Pyrex sleeve in proximity thereto, while the nitrite to be reacted is contained in an ultraviolet transmitting receptacle, such as a water-cooled Vycor immersion well.

A variety of solvents may be used for the photolysis of the nitrite, including acetic acid, acetone, acetonitrile, benzene, carbon disulfide, carbon tetrachloride, chlorobenzene, chloroform, cyclohexane, dimethyl ether, dimethylformamide, dioxane, ethylacetate, Freon 113, heptane, methylene chloride, and toluene, of these benzene and Freon 113 yield preferred results and toluene is the most preferred. For efiicient operation, the solvent is preferably chosen so as to have a high degree of transparency to ultraviolet radiation within the specified band of nitrite absorption.

While the solvents used in the photolysis are ordinarily water-free, a small amount of moisture in the solvent used for photolysis does not ordinarily interfere with the progress of the ultraviolet activation and rearrangement of the nitrite in accordance with the present invention.

During the course of the photolysis of a nitrite ester, a stream of nitrogen or other inert gas is generally bubbled through the solution, but it is not always necessary to keep the nitrite solution protected by an inert atmosphere.

The photolysis of the nitrite ester which is carried on by irradiation with the selected band of ultraviolet radiation is monitored from time to time by infra-red spectrophotometry of an aliquot, and the reaction is complete when the infra-red absorption spectra lack the characteristic spectra of the nitrite grouping.

The products of the nitrite photolysis are variously treated, and such subsequent steps may include chromatography, fractional crystallization, and by further reactions to convert the photolysed nitrite ester into a nitrile, iminolactone, lactone, hemiacetal, alcohol, carboxylic acid, or otherwise.

Among the various ultimate products which may be prepared from the steroid nitrites by the process of the present invention, with added conventional steps, are the lactones, linked at 2 and 19, at 4 and 19, at 6 and 19, at 11 and 18, at 11 and 19, at 18 and 20, and at 24 and 27, the

corresponding hemi-acetals substituted at the 2, 4, 6, 11,v

18, 19, 20, or 24 position and a Wide variety of other substituents at these positions.

Depending upon the exact conformation of the steroid nitrite (having 18 to 29 carbon atoms) involved and used during the photolytic process of the present invention, photolysis procedes With the transfer of the NO group of the nitrite grouping from one carbon atom to an adjacent carbon atom with the formation of an oXime or a nitroso-monomer or nitroso-dimer. While the exact mechanism of the photolytic reaction has not yet been fully established, it appears to involve several intermediate steps, but in all instances the process of the present invention involves the shifting of a nitrogen atom to 9 another carbon atom which is spaced from the original carbon atom to which the nitrogen was linked by two other carbon atoms, e.g., as the C-11 carbon is separated from the C-18 carbon atom by two intervening carbon atoms C-12 and C13.

It will be understood that the foregoing general description and the following detailed description as well are exemplary and explanatory of the invention but are not restrictive thereof.

In a manner similar to that described for the various foregoing preparations, the other hydroxy steroids having 18 to 29 carbon atoms, and constituting the estrogen, androgen, methyltestosterone, pregnane, cardiac aglycone, bile acid, cholesterol, ergosterol and stigmasterol series, may be reacted with a nitrosyl halide to form the corresponding nitrite esters.

Where there is more than one hydroxy group subjected to the formation of a nitrite ester by treatment with nitrosyl halide, such as the 16a-hydroxy group, it may be advantageous to start with a 16u-acylated compound which lacks the 11,8-hydroxy group to treat this compound microbiologically, as with Curvularia lunata (N.R.R.L. No. 2380) to produce the llfi-hydroxy group to be subjected to the formation of the llfi-nitrite ester. After photolysis, the 16a-acylate may be removed to give the l6a-hydroxy group.

Among the many steroid compounds having 18 to 29 carbons which may be nitrited to form nitrite esters are those having substituents or modification of the basic cyclopentanoperhydrophenanthrene ring structure.

Thus in the estrogens having 18 carbon atoms in the ring structure, at position 6,.there may be substituted a halogen or a methyl group; at position 9 there may be an a-fiuorine, or other halogen; at position 16, there may be an a-hydroxyl group; at position 17, there may be an a-hydroxyl group or an acetoxyl group; at position 18, there may be an aldehyde, a methyl group, a hydroxyl group, a carboxyl group, an amino-methyl group, or a cyanide group.

Additionally, in the androgens, having 19 carbon atoms in the ring structure, there may be a double bond from positions 1 to 2, and/ or from 4 to 5.

In the pregnane series, having 21 carbon atoms, in addition to the various substitutions and modifications set forth above, there may be additional substitutions of a hydroxyl or an acetate, butyrate or other carboxylate radical at the 21 position.

In the sterols, having 27 to 29 carbon atoms similar, usual substitutions may be made in the A, B, C, and D rings, or in the side chain.

The various nitrite esters of the 18 to 29 carbon series of steroids may be photolysed by irradiation in solution with ultra-violet light to form the corresponding oximes and nitrosomonomers or dimers by interaction with an available or reactive hydrogen atom in a conformationally adjacent position; that is, a nitrite radical at the 11,8 position may react with an available hydrogen atom in the 18 or 19 positions; a 2,8, 4,8 or 65 nitrite may react with an available hydrogen in the 19 position; a 1B, 18 or 19 nitrite with hydrogen in the 11 position; a 2004 or 205 nitrite with a hydrogen in the 18 position; an 110:- nitrite with hydrogen in the 1 position; a 7/3-nitrite with hydrogen in the -position; a 15 u-nitrite with a hydrogen in the 7 position; and a 24 nitrite with a hydrogen in the position. These oximes, and nitroso dimers, and monomers so produced may thereafter be reacted by conventional steps to produce the corresponding hemi acetals, nitriles, aldehydes, lactones, alcohols, carboxylic acids, carboxylates, as well as other derivatives, all of which have variously modified therapeutic properties with respect to their parent steroid compounds. In many instances, the properties are greatly enhanced with respect to the parent compounds, while in other instances the properties are greatly different, and in a few instances, the properties are antagonistic with respect to the properties of the parent compound. The immediate and ultimate products of the photolysis of the nitrite in accordance with the present invention have an exceedingly wide range of utility. Many of them are useful without further treatment after photolysis, while others may be modified to achieve their greatest present usefulness. When modified, they are useful as improved therapeutic agents, as intermediates providing new and more economical routes to known and to hitherto unknown compounds, as detergents, as perfume substances, as bacteriostats, and many other uses, some of which are hereinafter set forth in detail.

In general, the oxime is the most stable derivative obtained by photolysis, the isomeric nitroso derivative always being formed first and, under prototropic conditions, converted to the oxirne. When steroidal nitrite esters (e.g., the llfi-nitrite ester of l6fi-methyl-prednisolone acetate) are photolysed and the photolysed product is immediately subjected to separation, as by chromatography, an oxime (e.g., 1S-oximino-16/3-methyl-prednisolone acetate), is usually recovered with a small amount of the isomeric nitroso-dimer being present. Alternatively alkyl nitrite esters (e.g., l-octanol nitrite) upon photolysis and immediate separation of the photolysed product preferentially yields the nitroso-dimer (e.g., 4-nitroso-1-octanoldimer) with a small amount of oxime (e.g., 4-oximino-1 octanol) being present. In the latter case, the nitrosodirner converts under prototropic conditions to the more stable isomeric form, the oxime. This conversion takes place in the photolysed solution on long standing or may more rapidly be effected by warming the nitroso compound at moderate temperatures, usually in the range of 50-125" 0., either alone or in solution and preferentially in a refluxing solution of a lower alkanol such as methanol, ethanol, propanol, and the like. When the photolytic exchange of an NO with a hydrogen atom within the molecule of an HOCCXCH alcohol, produces a tertiary nitroso derivative, there is usually formed a nitroso-monomer. For example the nitrite ester of 3- cyclohexyl-l-propanol upon photolysis according to the process of this invention, yields the nitroso-monomer, 3(1- nitroso-l-cyclohexyl)-1-propanol. While the ox-ime,'nitroso-dimer and nitroso-monomer are usually formed by the photolytic process, in a few instances there is some subsequent formation of a nitrone.

The solvents for use in the photolysis are chosen pri marily on the basis of their ability to dissolve the steroid nitrite ester to be photolysed, and to a lesser extent upon the facility with which they may be removed by evaporation at moderate temperatures, so that the oximes, nitroso dimers or nitrones may be recovered as crystals without being subjected to a higher degree of heat than is necessary, which would tend to cause decomposition or deterioration of the photolytic products.

Thus, those solvents providing good solubility for the steroid products to be photolysed are preferred, and those having the additional characteristics of a relatively high molecular weight and a relatively low boiling point are the most desired. For this reason toluene is preferred above the other solvents, although benzene and Freon 113 are almost as advantageous. Among the many other solvents which may be used are acetone, acetonitrile, carbon disulfide, carbon tetrachloride, chloroform, chlorobenzene, cyclohexane, dimethyl ether, dimethylformamide, dioxane, ethyl acetate, heptane, methanol, methylene chloride, and xylene.

Any source of ultraviolet light which provides a strong radiation from about 2000 A. to 5000 A. is suitable, especially in the band from 3400 A. to 4000 A., and a mercury arc lamp, such as the 200 watt Hanovia mercury lamp is suitable, although larger lamps would be needed for eco-' nomical production on a larger scale. The nitrile solution to be irradiated is preferably contained within a water-cooled immersion well which is substantially transparent to ultraviolet light of the specified wave-lengths,

and for small quantities a water-cooled Vycor immersion Well is preferred.

Other sources of irradiation which may be used in the novel process of this invention are high energy irradiations such as X-rays, gamma-rays and the like.

To eliminate excessive heating of the nitrite during photolysis, the solution being irradiated is preferably surrounded by a filter which eliminates the non-actinic rays which could serve only to heat the solution. Thus, a sleeve of Pyrex glass is preferably provided around the solution undergoing photolysis.

After about 20 minutes of irradiation, in most instances, the photolytic product begins to precipitate from solution, and completion of the photolytic reaction can often be judged by visual examination of the volume of the precipitate, but for more careful control and a more accurate determination of the completion of the photolytic reaction, aliquot samples of the solution undergoing photolysis may be subjected to monitoring by periodic examination of their infra-red absorption spectra to determine the extent to which the nitrite ester has been activated and transformed into the desired reaction products. Conveniently, it is usually necessary only to examine the aliquot sample to determine the remaining quantity of nitrite ester, due to the difference which is readily apparent between the infra-red absorption spectra of the nitrite and the absorption spectra of the oximes, nitroso-dimers and nitrones.

In general, the photolysis of the organic nitrite esters is substantially complete after about 1 hour of irradiation under the conditions generally specified in toluene solution, at about 30 0, when irradiated by a 200 watt mercury arc lamp. This time may vary widely due to the difference in actual absorbed ultraviolet energy activating the dissolved nitrite.

The foregoing general description of the process of the present invention, and of the new compounds comprised in the present invention will now be illustrated by reference to a wide variety of specific working examples in which the nitrite esters are photolysed or transformed photochemically into other compounds which may be further treated to yield ultimate useful products.

Steroid nitrites according to the present invention may be prepared from the corresponding alcohols, and the following specific examples are typical of the preparation of steroid nitrites according to the present invention and for subsequent photolysis.

PREPARATION NO. E-l

llp-hydroxyestrone (Ela) is readily converted to the 3 acetate (Elb) and then to llB-nitrite of estrone by dissolving 3.0 g. of the llp-hydroxyestrone, by conventional process of acetylating the B-hydroxy group, as by treatment with an excess of acetic anhydride, and by evaporating the acetic anhydride in vacuo. Thereafter the 11;?- hydroxy estrone 3 acetate (Elb) is dissolved in 100 ml. of pyridine, and there is slowly added to the solution while stirring about 80 m1. of a 1% solution of nitrosyl chloride in pyridine. The addition is preferably made dropwise while the solutions are at a temperature of approximately C., and the addition is continued until the color of the solution remains unchanged by further additions of the nitrosyl chloride solution. After standing for an hour, the llfi-nitrite of estrone (Elc) may be precipitated from solution by the addition of water to the solution, and the llfi-nitrite may then be recovered by filtration.

PREPARATION NO. E-2

The llp-nitrite ester of estradiol (E2c) may be formed in exactly the same manner as set forth in Preparation No. E1, except that llfl-hydroxyestradiol (E2a) is first acetylated at C3 and C17, and is then treated with nitrosyl chloride to form the llfi-hydroxy nitrite ester of estradiol 3,17-diacetate (E2b).

(E-la) 0 ll W3 (E-lb) O H an AcO (E-lc) O [I TO (IE-2a) OH l lfi (Eqb) 0A0 (Ezc) 0A0 I li PREPARATION NO. E-3

(IE-3a) O H T U od .03 I

PREPARATION NO. B4

A stirred solution of 2.7 g. of llfi-hydroxytestosterone- 17-acetate (E4a) dissolved in 100 ml. of dry pyridine and cooled to about C. or lower, is treated with nitrosyl chloride by slowly adding about 50 ml. of a 1% solution in dry pyridine until a dark blue or green color persists in the mixed solutions. After about minutes, water is added to the reaction mixture to precipitate the product and to decompose any residual nitrosyl chloride. Filtration of the crystalline solid and recrystallization from methylene chloride gives the l l/i-nitrite ester of testosterone-17-acetate (E'4b) as crystalline white needles.

(IE-4a) OAG (M) one PREPARATION NO. E-S

(E-5n) O Ago- is PREPARATION NO. E-6

The 20-carbon compound, llfi-hydroxy-lh-methyl testosterone acetate (E-6a) is converted into the corresponding llB-nitrite (E-6b) by reacting it in dry pyridine 1% solution at about 30 C. with a 1% solution of nitrosyl chloride in dry pyridine, the addition being made slowly with stirring and continuing until the color of the solution remains unchanged. The llfi-nitrite ester is recovered after 30 to 60 minutes by water precipitation, filtering and washing.

(IE-6a) OAc PREPARATION NO. E-7

A 2.00 g. sample of 6B-hydroxy-3;3,2l-diacetoXy-20- keto-Su-pregnane (E-7a) in 200 ml. of pyridine at 30 C. is treated with an excess of nitrosyl chloride in pyridine solution and can be water-precipitated as a white solid which is recovered by filtering. It may then be recrystallized from hexane to give a white crystalline material, which is 35,21 diacetoXy-20-keto-5a-pregnane-6fi-nitrite (E7b).

(E-Gb) PREPARATION NO. E8

The llli-nitrite of cortisol acetate (E-Sa) is readily formed in essentially quantitative yield by titrating a 1% solution of nitrosyl chloride into a solution of 4.0 g. of cortisol acetate (E-8a) dissolved in ml. of dry pyridine, the solution being cooled to about 0 C., and the nitrosyl chloride being added while the solution is stirred. The addition of the nitrosyl chloride is continued until the blue-green color of the solution remains substantially unchanged. Thereafter, the llfl-nitrite ester of cortisol acetate is precipitated from the pyridine solution by the addition of water, and the nitrite is recovered by filtration. On recrystallisation from a volatile solvent such as methylene chloride, the cortisol acetate llfl-nitrite (E- 8b) is a crystalline product.

CII OAO PREPARATION NO. E-9

Dissolve 3.0 g. of corticosterone acetate (E-9a) in 100 ml. of dimethylformamide and cool to 10 C. While stirring, 55 ml. of a 1% solution of nitrosyl chloride in dimethylformamide is slowly added until the color of the solution remains substantially constant. The solution is allowed to stand for an hour or more and the llfi-nitrite ester (E-9b) is precipitated from the solution by the addition of water to the mixture. The precipitate is then recovered by filtration, washed with water and may be purified by recrystallization from a solvent such as methylene chloride. The resulting product is the 11 8-nitrite ester of corticosterone acetate.

(EM) cmoac PREPARATION NO. E-lO In exactly the same manner as set forth in Preparation No. E9, the 11,8-nitrite ester of corticosterone acetate may be prepared using about 85 ml. of a 1% solution of nitrosyl bromide in place of the nitrosyl chloride solution.

(II-9b) PREPARATION NO. E-ll A stirred solution of 2.5 g. of 16u-hydroxycorticosteronediacetate (E-l 1a) dissolved in 100 ml. of dry pyridine and cooled to about -20 C. is treated with nitrosyl 0:0 HO{/\ ---OAc cnzoxc PREPARATION NO. E-12 16a-methyl corticosterone acetate (E-12a) is subjected to exactly the same treatment as is set forth with respect to Preparation No. E-ll.

ONO CH3 05 PREPARATION E- l 3 (IS-12b) (1343) CHQOAC In exactly the same manner as set forth in preparation No. E-18, the llfi-nitrite ester of prednisolone acetate may be prepared using about 100 ml. of a 1% solution of nitrosyl bromide in place of the nitrosyl chloride solution.

PREPARATION NO. E-20 (E-20a) CH3 PREPARATION NO. E-21 A solution of 4 g. of llfi-hydroxyprogesterone (Er-21a) in 100 ml. of dry pyridine cooled to about 20 C. is constantly stirred while nitrosyl chloride is allowed to distill into the steroid solution until the color of the nitrosyl chloride persists. Thereafter, water is added to precipitate the 11 fi-nitrite ester of progesterone (E-21b) formed by the reaction of the nitrosyl chloride with the 11/8- hydroxy steroid. The crystalline precipitate is then filtered, washed, and dissolved in and recrystallized from a volatile solvent, such as methanol, methylene chloride or hexane.

(IE-21a) CH3 i= T O (E21b) CH3 m -QU '20 PREPARATION NO. E-22 The llfl-nitrite of 16a-hydroxyprednisolone diacetate (E-22c) is readily formed in essentially quantitative yield by first acetylating 16a-hydroxyprednisolone (E-22a) to block the 16a-hydroxy group, after which the acetylated product, 16a-hydroxyprednisolone diacetate (E22b), is reacted by titrating a 1% solution of nitrosyl chloride into a solution of 3.0 g. of 16a-hydroxyprednisolone diacetate dissolved in ml. of dry pyridine, the solution being cooled to about -5 C., and the nitrosyl chloride being added While the solution is stirred. The addition of the nitrosyl chloride is continued until the blue-green color of the solution remains substantially unchanged. Thereafter, the llfi-nitrite ester (E-22c) of acetylated 16a-hydroxyprednisolone acetate is precipitated from the pyridine solution by the addition of water, and the nitrite is recovered by filtration.

CH OAO PREPARATION NO. E-23 Dissolve 3.0 g. of the 22 carbon steroid, 16a-methylprednisolone acetate (E-23a) in 100 ml. of dirnethyl formamide and cool to 10 C. to -25 C. While stirring, add 55 ml. of a 1% solution of nitrosyl chloride in dimethyl formamide slowly until the color of the solution remains substantially constant. The solution is allowed to stand for an hour or more and the llfi-nitrite ester is precipitated from the solution by the addition of water to the mixture. The precipitate is then recovered by filtration, and may be purified by recrystallization from a solvent such as methylene chloride. The resulting product is the llfl-nitrite ester of a 16a-methylprednisolone acetate.

ornoAc 1 7 PREPARATION E-14 CHzOAG HO Q3 GHQOAC PREPARATION E-15 CH OAc (IE-15b) PREPARATIONS NOS. E-13, E-l4, E15 AND El6 CH20AO Of U 18 PREPARATION E-17 A solution of 2.5 g. of pregnane-3u-1l,8-17u-20,B-tetro1, 3,20-diacetate (E-17a) in ml. of dry pyridine cooled to about -20 C. is constantly stirred while nitrosyl chloride is allowed to distill into the steroid solution until the color of the nitrosyl chloride persists. Thereafter, water is added to precipitate the llfi-nitrite ester of pregnane-3a,1lfl,17a,20;3-tetrol, 3,20-diacetate (E-17b) formed by the reaction of the nitrosyl chloride with the llli-hydroxy steroid. The crystalline precipitate is then filtered, the filtrate washed, and dissolved in and recrystallized from a volatile solvent, such as methanol, methylene chloride or hexane.

CH JHOAc 93 AcO- (E-17b) CH3 lHOAe (Pregnane-3a,11,6,17a,20fl-tetrol 3,20-diacetate requires no preliminary acetylation to block the hydroxy group at l7u-position, as the 17a-hydroxyl group is relatively inactive with respect to nitrosyl chloride nitriting.)

PREPARATION NO. El8

Dissolve 3.0 g. of prednisolone acetate (E-18a) in 100 ml. of dimethylformamide and cool to -10 to -25 C. While stirring, add 60 ml. of a 1% solution of nitrosyl chloride in dimethyl formamide slowly until the color of the solution remains substantially constant. The solution is allowed to stand for an hour or more and the nitrite ester (E-18b) is precipitated from the solution by the addition of Water to the mixture. The precipitate is then recovered by filtration, and may be purified by recrystallization from a solvent such as methylene chloride. The resulting product is the llp-nitrite ester of prednisolone acetate.

(E-lSu) (IDHQOAO @348") ornoAe onloAc PREPARATION NO. E24

In exactly the same manner as set forth in Preparation No. E-l8, the 11,8-nitrite ester of 16/8-methylprednisolone acetate (E-24b) may be prepared starting with a solution of 16,8-methylprednisolone acetate (E-24a).

(IE-24a) PREPARATION NO. E-25 A stirred solution of 3.0 g. of dexamethasone 21 acetate (E-25a) dissolved in 100 ml. of dry pyridine and cooled to about -20 C. is treated with nitrosyl chloride by slowly adding about 50 ml. of a 1% solution in dry pyridine until a dark blue or green color persists in the mixed solutions. After about 5 minutes, water is added to the reaction mixture to precipitate the product and to decompose any residual nitrosyl chloride. Filtration of the crystalline solid and recrystallization from methylene chloride gives the llfi-nitrite ester of dexomethasone 21 acetate (E-25b), i.e., 9oz fluoro-16ot-methyl-A -pregnadiene-3,20- dione-11B,17a,21-triol l1-nitrite 21-acetate.

A we

22 PREPARATION NO. E-26 In exactly the same manner as recited for Preparation No. E-25, one may form 9u-fluoro-1GB-methyl-AL pregnadiene-3,20-dione-11,8-17a,21-trio1 l l-nitrite 21-acestate (E-26b) from the 16,8-methyl isomer of dexamethasone acetate (E-26a).

(IE-26a) CHQOAO (El-26b) PREPARATION NO. E-27 A solution of 3.0 g. of pregnane 3a,11p,2-05-t-riol-3,20- diacetate (E-27a) in ml. of dry pyridine cooled to about -ZO C. is constantly stirred while nitrosyl chloride is allowed to distill into the steroid solution until the color of the nitrosyl chloride persists. Thereafter, water is added to precipitate the llB-nit-rite ester of pregnane-3a, 1'1fl,20 3-tri0l-3,20-diacetate (E-27b) formed by the reaction of the nitrosyl chloride with the 11 ,B-hyd-roxy steroid. The crystalline precipitate is then filtered, Washed, and dissolved in and recrystallized from a volatile solvent, such as methanol, methylene chloride or hexane.

(E-27a) CH3 IJHOAc PREPARATION NO. E28

1 water, and the nitrite is recovered by filtration. On recrystallization from a volatile solvent such as methylene chloride, the cholestanol 3 acetate llB-nitrite is a crystalline product.

omfjfi .0313

PREPARATION NO. E-29 (IE-28a) (IE-28b) (IE-29b) (EHZOAG M l O PREPARATION NO. 13-30 HO o (IE-30b) PREPARATION NO. E-31 Similarly, 4,5-oxido-dihydrocorticosterone acetate (E- 3la) is prepared by treatment of corticosterone acetate with pe-rphthalic acid, after which treatment in pyridine with an excess of nitrosyl chloride yields the llfi-nitrite ester (E-31b) of the steroid, which may then be separated and recovered by precipitation and filtering.

ornoxc 3 :0 W IQ o (E'31b) CHgOAC 3 :0 "tlfi PREPARATION NO. E-32 2.3 grams of 20fi-hydroxy-A -pregnen-3-one (E-32a) in 16 m1. of pyridine at -30 C. moisture free, is reacted while stirring with dropwise additions of a 20% solution of nitrosyl chloride in dry pyridine. Each drop is decolorized until all of the alcohol has been reacted at which time, the addition of another drop of nitrosyl chloride solution causes the reaction mixture to remain blue. Stirring is continued for several minutes, after which the reaction may be quenched by the addition of ml. of ice water, thereby precipitating the A -pregnen-3-one-20/3- nitrite (E- 32b) which is filtered and washed with water and dried.

(E-32a) CH3 1 CHOH no ta PREPARATION NO. E-33 The 23 carbon, strophanthiodol 3-acetate (E-33a) may be converted into 19-nitrate ester (E-33b) by treatment with an equimolar nitrosyl chloride in the same manner as for Preparations E-8 or E-32.

PREPARATION NO. E-34 The 24 carbon, 3a-hydroxy-1l-ketocholanic acid (E- 34a) may be used to form the 24-nitrite ester by subjecting the acid to conventional lithium-aluminum hydride reduction to form the corresponding 3oc-11fi-24-12rio1 (E-34b) which is then acetylated to form the 3,24-diacetate ('E 340), followed by half-hydrolyzation to leave the 3-acetate-11,8-24-d-iol, which is then subjected, in pyridine solution to treatment with a slight excess of nitrosyl chloride to form the 3a-acetoxy-11fl-hydroxy-cholane-24-nitrite (E-34d). The nitrite ester is then recovered according to the procedures set forth above for other nitrite esters.

E-34a H 0 0 OH oh M Hap Haw mofomoltc l fi C omorro toy PREPARATION NO. E-35 (IE-35a) CH3 A s.

HO (El-35b) l HO- OH OOC!Q (Fl-35d) PREPARATION NO. 13-36 Desmethyl-oxocholesterol (E-35a) may also be used as the starting material for the formation of a 26-carbon nit-rite ester in which case desmethyloxocholesterol is first subjected to a Wolfi-Kisehner reduction to rid it of the keto radical at the 25 position, thereby forming the 26- carbon, 26-nor-cholesterol E-36b). This substance is converted into 6/3-hydroxy-26-nor-cholestan-iafl-yl acetate $(E-36c) which is then dissolved in pyridine and treated with an excess of a pyridine solution of nitrosy-l chloride, thereby yielding the 613-nitrite este of 26-nor-cholestanol on Mang PREPARATION NO. E-37 3-acetoxy-6fl-hydroxy cholestane (E-37a) may be reacted with nitrosyl chloride to form the nitrite ester (E-37b) under the same conditions as set forth above.

PREPARATION NO. 1-3-38 1 1B-hydr0xyergost-22ene-3 3-01-3acetate (E-38a) may likewise be treated with nitrosyl chloride to form the (El-38a) Ergostero1 (E-39a) itself may be reacted to form a nitrite by first acetylating it at the 3 position by conventional treatment with acetic anhydride (E-39b), following by treatment with perphtha-lic acid to give A ergostadiene-3fl-5a-6B-trio1 3 acetate (E-39c) which is similarly reacted with nitrosyl chloride to form the 6finitrite. (E39d) I (mow/W51? PREPARATION NO. E-39 29 PREPARATION NO. 13-40 An example of the formation of a nitrite ester of a 29 carbon steroid is found in the treatment of stigmasterol (El-40a) which is first a-cetylated to yield stigmasterol acetate (E-40b) which is nitrated by treatment with furning nitric acid after which the nitro compound (E-40c) is reduced With Zinc dust in the presence of water to form 6-ketostigrnast-22-eny1 acetate (E40d). Reduction with sodium borohydride in ethanol-tetrahydrofuran solution yields 6fl-hydroxystigmast-ZZ-enyl acetate. This product may then be formed into the 6B nitrite ester by treatment in pyridine solution with nitrosyl chloride.

HO l

CZHB A- i A00C l lo:

igjgf I AcO- v 30 (E-4Uf) x oh I/\ A00- ONO PREPARATION NO. E-41 The nitrite ester of ZB-hydroxy-cholestanyl acetate is formed When ZB-hydroxycholestanyl acetate is reacted With nitrosyl chloride in pyridine solution at room temperature or at lower temperatures. The procedure may be the same as has been set forth above in connection With Preparation N0. E8, for instance.

PREPARATION NO. E-42 In the identical manner, the nitrite ester of 4,8-hydroxycholesteryl acetate may be formed starting with 4fi-hydroXy-cholesteryl acetate in place of 2,8-hydroXy-choles tanyl acetate.

(ID-42b) ONO PREPARATION NO. E-43 Isorubijervine is first converted to the S-acetate by treatment with acetic anhydride, after which the nitrite ester 31 may be formed at the 18 position by treatment of the 3- acetate with nitrosyl chloride in pyridine solution, followed by precipitation filtration and washing, yielding isorubijervine-3-acetate-l8-nitrite.

ONOCH W The various compounds set forth above may be photolyzed and further converted into various other intermediates and final compounds in accordance with the general procedures set forth above, and more specifically set forth below.

Photolysis Example E] The 11 fl-nitrite of estrone (E-lb) resulting from Preparation No. E-l, is dissolved to form a 2% solution in toluene, and is irradiated at a temperature of from to 40 C., preferably at about 30 C., for a period of 30 to 60 minutes, the solution being agitated by bubbling nitrogen through it. The preferable form of the apparatus employed for the irradiation is that set forth above and comprises the 200 watt Hanovia highpressure mercury arc lamp, provided with a Pyrex sleeve, with the solution contained in an ultra-violet transmitting receptacle, such as a water-cooled Vycor immersion well. The nitrite in solution is thus subjected to ultra-violet radiation from 3000 A. to 4500 A., especially in the band of 3400 A. to 400 A. During the irradiation, the progress of the photolysis is monitored by infra-red spectral observation of the absorption bands of a small sample of the photolysed mixture so as to determine when the characteristic absorption spectrum of the nitrite radical has substantially disappeared.

The photolysed solution comprises 3-acetoxy-11B-hydroxy-l8-oximinoestrone (Elc) which may be purified by chromatography after the toluene solvent has been evaporated by bubbling air through the solution or by boiling under reduced pressure. For the chromatographic separation, the column may be filled with Florosil, and the elution may be carried out using ether-benzene mixtures containing increasing quantities of ether; the oxime being eluted when the concentration of the ether in the developing solvent reaches beyond about 30%. Thereafter, the solvent fractions containing the 18-oxirne may be evaporated to yield crystals of the 18-oxime, after 32 which the 18-oxime may be purified by recrystallization from ethyl acetate and then from ethyl alcohol.

The purified 18-oxime (E-lc) may then be converted to the corresponding hemiacetal (E-ld) by dissolving it in about 10 times its weight of glacial acetic acid, after which there is added about one-fourth volume of a 5% solution of sodium nitrite. Gas is evolved, and after shaking for a few minutes white crystals separate, which may be purified by recrystallization from a suitable solvent, such as methanol.

The 11-18 hemiacetal of estrone-3-acetate exhibits enhanced estrogenic physiological activity, resulting in proliferation of endometrium, inhibition of pituitary follicular stimulating hormones and lowers serum cholesterol. It usually exhibits greater activity when given orally, than when administered parenterally.

( I 'IOH All AcO-

Photolysis Example E-Z IAQ Photolysis Example E-3 A -androstene-3-17-dione nitrite (E-3b) may be converted to the corresponding 18-oxime compound (E-Zc) by following the procedure given in Photolysis 33 Example E-l, and may then be converted to the 11-18 hemicetal by the subsequent steps set forth above, and purified by recrystallization from methanol.

A androstene-3-17-dione-11-18 hemiacetal (E3d) exhibits enhanced androgenic activity with respect to 11 hydroxy-A -androstene-3-17-dione, as well as enhanced anabolic activity, and is useful in promoting a positive calcium balance in osteoporosis. It may be efiectively administered orally, as compared with llfl-hydroxy-A androstene 3 17 dione which is substantially inactive when given orally.

Photolysis Example E-4 The llfi-nitrite ester of testosterone-17-acetate (E-4b) when treated in accordance with Example E-l, yields the photolytic product, 1lfi-hydroxy-18-oximinotestosterone- 17-acetate (E-4c) which may be further converted to 11 3-hydroxy-1S-aminotestosterone-17-acetate by conventional treatment with lithium-aluminum hydride followed by reoxidation with manganese dioxide.

If desired the 18-amino compound (E-4d) may be further reacted to convert it into the corresponding quaternary ammonium salt (E-4e) which is useful as a sympatholytic .agent acting by ganglionic neural transmission, and which is also useful as an anti-spasmodic. The 18- amino compound may be converted to the quaternary ammonium salt by treating the IS-amino compound with methyl iodide and with mild heat.

(IE-3d) NOE Photolysis Example E-5 A 1% solution of androsterone-3-acetate-1lfi-nitrite (E-Sb) in Freon 113, irradiated by ultraviolet light under the conditions specified in Example E-1 for a period of about 1 hour yields a product which comprises the 18 oxime of androsterone-3-acetate (E'5c), which can be purified and separated by recrystallization, and the 19- oxime of androsterone-B-acetate which is isolated by means of chromatographic techniques.

The parent compound llfi-hydroxy androsterone-3- acetate (Er-5a) is a weak androgen, While the androsterone-l1-18-hemiacetal-3-acetate (E-Sd) lowers the serum cholesterol when administered intramuscularly. The androsterone-l1-18-hemiacetal may be prepared from the photolytically produced oxime (E-S'b) by mean of nitrous acid followed by mild alkali treatment, such as aqueous sodium carbonate.

(E-5c) NOH Photolysis Example E-6 From the preparation No. E-6 is derived 17a-methyltestosterone-acetate-l lfi-nitrite (E-6b) which is subjected to photolysis according to the procedure set forth in Example E-l, by which there is produced the 18-oxime compound (E-6c). By reaction with aqueous sodium nitrite in glacial acetic acid solution, this 18-oxime is converted into the 11-l8-hemiaceta1 (E-6d). When recrystallized from methanol or other suitable solvent it has the same general properties as l7a-methyl testosterone acetate, but with enhanced androgenic activity, and it also has the property of inhibiting pituitary follicular stimulating hormones in the human system.

(E-Gc) NOE lA I S :03

Photolysis Example E-7 The 6 3-nitrite of 3/3, 2l-diacetoXy-20-keto-Sa-pregnane (E-7b) dissolved in toluene to form a 3% solution is photolysed under the conditions given above for one hour. After photolysis, the solution is allowed to stand for several hours, and a very small amount of iso-propyl alcohol is added to the solution to convert any nitroso-dimer to the oxime. The solid precipitate was dissolved in methylene chloride and was chromatographed on a Florosil column, which was then eluted with successive portions of methylene chlorideacetone, the successive portions containing increasing amounts of acetone, the 19- oxime (E-7c) being found in the intermediate fractions of the eluate. Thereafter, the 19-oxime is recrystallized from acetonitrile and is then ready for further treatment.

The l9-oxime (E-7c) is then dissolved in glacial acetic acid to which is slowly added a dilute aqueous solution of sodium nitrite, thereby forming 6,19-hemiacetal of 35,652l-trihydroxy-ZO-keto pregn-19-al 3,21-diacetate (El-7d), which may be purified by recrystallization from methanol-acetonitrile.

Photolysis Example E-8 Under conditions identical with those of Example E-l, a 1% solution of cortisol acetate llfi-nitrite (E8b) prepared according to Preparation E-S, yields the l8-oxime of cortisol-Zl-acetate (E-8c) which may be converted to 1l-18-hemiacetal of cortisol-21-acetate (E-8d), as described above.

The hemiacetal prepared from the 18-oxime of cortisol acetate has enhanced anti-inflammatory activity with respect to its parent compound, is an anti-anabolic agent, is useful in the treatment of collagen diseases, rheumatoid arthritis and asthma, Lupus erythematosis and various skin dermatoses, atopic dermatitis and pemphigus.

NOH

CH2OA0 (E-Bc) Photolysis Example E9 Corticosterone acetate llfi-nitrite (E-9b) may be converted into aldosterone by photolysis and subsequent chemical treatment, as follows:

Corticosterone llB-nitrite 2l-acetate in dry toluene (3% concentration) is irradiated under the conditions set forth above in connection with Example E-l, at about 40 C. After about 20 minutes separation of a solid begins and this separation seems to be complete after about 40 to 60 minutes. The crystalline solid is removed by filtration and is the 18-oximino-115,21-dihydroxypregn-4-ene-3,20-dione 2l-acetate. It is added at about 10 C. to 5 to 10 times its weight of glacial acetic acid, after which there is added about 3 to 5 times its weight of a 5% aqueous solution of sodium nitrite. The mixture elfervesces and the oXi-me is rapidly dissolved. The solution is tehn allowed to warm to room temperature, is then diluted with water, made slightly alkaline with sodium bicarbonate, and is then extracted with methylene chloride. The extract is then dried with sodium sulfate and is evaporated to give a colorless gum which may be crystallized from ethyl acetate to give aldosterone 21? acetate (E-9d) which if desired may be converted to aldosterone (E-9c) (E-9c) IFIOH CHzOAG CH OAc (E-Qe) OH o-oH onion Aldosterone, as is known, may be used in the treatment of Addisons disease, and other disorders involving adrenal insufficiency.

Photolysis Example E-10 The Il s-nitrite ester of corticosterone Zl-acetate re-. sulting from the reaction of the steroid with nitrosyl bromide may be subjected to the identical reactions specified in Example E-9, with the production of an identical product.

Photolysis Example E-Il The H S-nitrite ester of 1fia-acetoxycorticosterone 21- acetate (E-llb) is photolysed under the conditions specified in Example E-l, and yields the 18-oxime, which may be chemically converted into the 11-18 hemiacetal of 16ot-acetoxycorticosterone 21-acetate (E-lld).

This resulting compound is useful as an aldosterone antagonist, and promotes a diuresis loss of both sodium and water.

Photolysis Examples E-12, 12-13, E-14, E-15 and E-16 Under procedures which are identical to those specified for Example E-ll, other derivatives of corticosterone acetate-llp-nitrites may be converted into their corresponding hemiacetals, all of which are useful in much the same fields as the 11-18 hemiacetal of 16a-acetoxycorticosterone ZI-acetate (E-lld), exhibiting properties as aldosterone antagonists and promoting diuresis loss of both sodium and water.

Thus by photolysis and subsequent treatment with nitrous acid:

E-12: 16a-methylcorticosterone acetate llfl-nitrate (E'- 12b) is converted to 18-oximino-16u-methy1corticosterone-llfi-nitrite (E-12c) which may then be converted to the 11-18 hemiacetal of 16ot-methylcorticosterone 21-acetate (E-12d).

E-l3: lfi 3-methylcorticosterone acetate llfl-nitrite (E- 13b) is converted to 18-oximino-l6fl-methylcorticosteronellfi-nitrite (E-13c) which may then be converted to the 1'1-18 hemiacetal of 16fl-methylcorticosterone 21-acetate (E-13d).

E-14: 16a-acetoxy-l-dehydrocorticosterone acetate 11pnitrite (El-14b) yields the l8-oximino compound (E- and finally the 11-18 hemiacetal (E-14d).

E-15: 16ct-methyl-l-dehydroCorticosterone-Zl-acetate llfi-nitrite (E-lSb) yields the 18-oximino compound (E- and finally the 11-18 hemiacetal (E-lSd).

E-16: 16 3-methy1- ldehydro'corticosterone-Zl-acetate llfi-nitrite (E-16b) yields the 18-oximino compound (E- and finally the 1l-18'hemiacetal (E-16d).

(E-12c) NOH CHzOAG 1 HO|/\ "CH3 OH o-en CH OAe =0 l g d (E-13c) r ton CHQOAQ 1 =0 l Hof: Ton;

(E-13d) 0H CH OAe (E-14c) NOH GHQOAO l --OAc (E-Md) (Fr-15d) CHIOAG Photolysis Example E-17 This compound (Ff-17d) is useful when intramuscularly administered as a therapeutic agent, as a pyrogenic agent and as an adjunct in the treatment of tertiary syphilis.

( -17) IfiIOH HOAO I..... HO-fij 1 I HOAc M I Q AcOMC Q Photolysis Example 13-18 The llB-nitrite ester'of prednisolone acetate (El-18b) may be photolysed in the manner set forth above to yield the corresponding l8-oxime (E-lSc), which may then be treated with nitrous acid while in acetic acid solution to form the 11-18 hemiacetal (E-18d), which is useful in much the same manner as its parent compound, prednisolone, and is somewhat more active than cortisol acetate.

The 18-oxime (E-18c) may be converted to the corresponding lactone (E-l8e) by treatment of the oxime in acetone solution with chromic acid acetone solution. The lactone (E-l8e) is then purified by recrystallization and yields a product which is a natriuretic agent leading to the loss of sodium in the human body and which also promotes osmotic diuresis. 

1. A STEROID NITRITE ESTER HAVING 18 TO 29 CARBON ATOMS IN THE STEROID MOIETY THEREOF, THE NITRITE RADICAL OF SAID NITRITE ESTER BEING CONFORMATIONALLY ADJACENT OT A HYDROGEN ATOM, THERE BEING A 2-CARBON BRIDGE BETWEEN THE RESPECTIVE CARBON ATOMS BEARING THE NITRITE ESTER AND THE CONFORMATIONALLY ADJACENT HYDROGEN ATOM, SAID NITRITE ESTER BEING IN A POSITION SELECTED FROM THE GROUP CONSISTING OF 1B,2B,4B,6B, 7B,11, 15A, 18,19, 20 AND 24; SAID STEROID NITRITE ESTER BEING FURTHER CHARACTERIZED IN THAT UPON IRRADIATION WITH ULTRAVIOLET LIGHT, THE NITRILE RADICAL UNDERGOES PHOTOLYTIC EXCHANGE OF POSITION WITH THE AFORESAID CONFORMATIONALLY ADJACENT HYDROGEN ATOM.
 16. 4-PREGNENCE-20B-OL-3-ONE 20 NITRITE. 